Alzheimer's disease is specific to human beings. It takes 10 years or more before its onset so that development of human disease model animals is desired in order to elucidate the cause of its occurrence or treat it. Alzheimer's disease (also called “Alzheimer type senile dementia”) is macroscopically characterized by atrophy of the brain, in particular, atrophy of temporal lobe while under microscope, it shows pathological changes characteristic mainly of neurofibrillary tangles and senile plaques. Neurofibrillary tangles (NFT) are neuronal inclusions composed mainly of phosphorylated tau protein. Neurofibrillary tangles are observed in sites where neurons are abolished, besides in Alzheimer's disease, in neurodegenerative disorders with dementia (frontotemporal type dementia Parkinsonism-17 (FTDP-17) (Poorkaj, P. et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825 (1998)), Down's syndrome and several other neurodegenerative disorders). From this it is said that formation of neurofibrillary tangles is a common cascade in all the disorders that involve neurodegeneration. In other words, the formation of neurofibrillary tangles represents a final common pathway that leads to abolition of neurons in Alzheimer's disease and other neurodegenerative disorders with dementia (Spillantini, M. G. & Goedert, M. Tau protein pathology in neurodegenerative diseases. Trends Neurosci 21, 428–433 (1998)). Therefore, inhibition of neurofibrillary tangles is considered to be one of treatments for all the neurodegenerative disorders inclusive of Alzheimer's disease. However, generation of mice that cause neurofibrillary tangles has hitherto been tried using overexpression of mutant human amyloid precursor protein (Games, D. et al., Alzheimer-type neuropathology in transgenic mice overexpressing V717 β-amyloid precursor protein, Nature 373, 523–527 (1995) and Hsiao, K. et al., Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice, Science 274, 99–102 (1996)) or human wild-type tau protein (Tau), and although senile plaques was formed or tau protein was accumulated within cells, no neurofibrillary tangle was observed in either case. That is, although animals that express an amyloid precursor protein and presenilin were generated as a model animal for Alzheimer's disease, they did not exhibit neurofibrillary tangles which represent pathological change in dementia although they exhibit senile plaques like humans.
Also, it has been tried to generate a transgenic mouse that expresses wild human type tau protein (tau) and three lines of transgenic mice have been reported. In the transgenic mice, (1) 4 repeat tau cDNA driven by Thy-i promoter (Gotz, J. et al. Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J. 14, 1304–1313 (1995), (2) 3 repeat tau cDNA driven by 3-hydroxy-3-methylglutaryl coenzyme A reductase promoter (Brion, J. P., Tremp, G. & Octave, J. N. Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer's disease. Am. J. Pathol. 154, 255–270 (1999)), (3) 3 repeat tau cDNA driven by prion protein promoter (Ishihara, T. et al., Age-dependent emergence and progression of a taupathy in transgenic mice overexpressing the shortest human tau isoform. Neurone 24, 751–762 (1999)) have been respectively used as a transgene.
It has been reported that among the three lines, the neurons in the lines (1) and (2) expressed approximately a 2-fold increase in tau and exhibited pretangle neuropathology while the neurons in the line (3) expressed a 5 to 10-fold increase in tau and the tau inclusions were observed in the neurons. However, none of the lines exhibited tau aggregations that showed birefringency after Congo red staining or thioflavin-S reactivity and did show formation of filamentous tau aggregations, i.e., neurofibrillary tangles.
On the other hand, there has been a report that in the mutant tau protein observed in FTDP-17, valine, which is amino acid at residue 337 is substituted with methionine (V337M) (Poorkaj, P. et al., Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825 (1998)).
However, no report has been made on the generation of a transgenic mouse that expresses mutant human tau.